This project addresses the mechanism, regulation and functional significance of immunoglobulin (Ig) uptake buy human vaginal and cervical epithelial cells, and the potential use of this mechanism to enhance the efficacy of topically administered vaginal microbicides containing antibodies for the prevention of STDs. Specific Aim 1 focuses on the mechanism of IgG and monomeric IgA uptake by vaginal and cervical epithelial cells. Tissue explants and polarized/stratified epithelial cell cultures will be used to determine: 1) whether Ig uptake is directional, 2) the intracellular localization of Ig, 3) Ig retention kinetics, and 4) Ig cervical epithelial cells. Immunohistochemical studies will determine whether Ig receptor expression and uptake of IgG or mIgA in vivo is related to hormonal changes during the menstrual cycle or to inflammatory conditions. Parallel studies will be conducted in vitro at protein and mRNA levels using hormone and cytokine treated epithelial cell lines. Specific Aim 3 will address the physiological relevance of intracellular Ig. Epithelial cells will be treated with human monoclonal antibodies/plantibodies that have neutralizing activity against pathogens that infect epithelial cells in vitro (HSV-2, chlamydia and HIV-1), or bind to human leukocyte antigens (ICAM1, SPA1); subsequent Ig-treated and untreated cells will be challenged with the respective pathogen(s) in cell- free (HSV-2, chlamydia, HIV-1) or cell-associated (HIV-1) form and inter- and intracellular antibody-mediated protection will be monitored. This project will also provide immortalized cell lines and human genital tract issues for the performance of other studies in the Topic Microbicide Program Project.